AB0030 OSTEOMODULIN DOWN-REGULATION IS ASSOCIATED WITH OSTEOARTHRITIS DEVELOPMENT
Authors: J. Zappia, Q. Tong, R. Van der Cruyssen, F. M. F. Cornelis, C. Lambert, T. Pinto Coelho, J. Grisart, E. Kague, R. Lories, M. Muller, D. Elewaut, C. Hammond, C. Sanchez, Y. Henrotin
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is associated with metabolic and structural changes in all joint tissues. Subchondral bone sclerosis, cartilage degradation, and synovial inflammation are the main hallmarks of OA [1–3]. OMD is a keratan sulfate proteoglycan, a member of the small leucine-rich proteoglycan (SLRP) family. OMD was first identified in bone where it is involved in the mineralization process [4,5]. Our previous work demonstrated that in the secretome of osteoblasts, OMD was one of the most differentiating factors between osteoblasts originating from the sclerotic and non-sclerotic zone of OA subchondral bone [3]. OMD levels were lower in the supernatant of osteoblasts coming from the sclerotic area. <h3>Objectives</h3> The present work examined if OMD is involved in bone and cartilage changes occurring during skeletal development and in OA. <h3>Methods</h3> We used <i>Omd</i> knock-out (KO) or overexpressing male mice and mutant zebrafish to study <i>in vivo</i> the impact of OMD on skeletal development and aging. We investigated the influence of OMD on the severity of cartilage and bone damage induced by destabilization of the medial meniscus in these mice. We also analyzed the animals' gait using the CatWalk XT system. The effect of OMD on gene expression by human trabecular osteoblasts in monolayer culture was analyzed by RNA sequencing method. Finally, OMD binding to RANKL was assessed using a solid phase binding assay. <h3>Results</h3> In wild-type mice, we identified OMD mainly in bone and calcified cartilage. Tibial growth plate significantly decreased in all genotypes with age but to a lesser extent in the KO mice than in other genotypes. In KO mice, the calcified cartilage layer was thinner in the medial tibial plateau and thicker in the tibial lateral plateau than in the wild-type, while total cartilage thickness was not different between genotypes. We also demonstrated that <i>Omd</i> deficiency led to thicker and less porous bone and subchondral bone sclerosis. <i>Omd</i> knock-out mice spontaneously developed more severe OA cartilage lesions in the medial tibial plateau than the wild-type during aging. In contrast, OMD production did not influence cartilage and bone changes induced by median meniscus destabilization. The gait pattern of mice was abnormal in KO compared to the wild-type genotype with a shorter swing and a smaller paw contact intensity. <i>omd</i><sup>-/-</sup> zebrafish developed more severe cartilage lesions than wild-type. In osteoblasts culture, OMD down-regulated some genes involved in the extracellular matrix organization and up-regulated other genes responsible for the collagen network degradation. Finally, OMD bound to RANKL and inhibited osteoclastogenesis. <h3>Conclusion</h3> Alterations of the OMD expression modify bone and cartilage metabolism and structure. OMD helps to preserve bone and cartilage integrity and a local decrease in its production leads to the development of OA mainly by increasing subchondral bone sclerosis and thinning the calcified cartilage. <h3>References</h3> [1]Maruotti N, Corrado A, Cantatore FP. Osteoblast role in osteoarthritis pathogenesis. J Cell Physiol. 2017;<b>232</b>. doi:10.1002/jcp.25969 [2]Stewart HL, Kawcak CE. The importance of subchondral bone in the pathophysiology of osteoarthritis. Front Vet Sci. 2018;<b>5</b>. doi:10.3389/fvets.2018.00178 [3]Sanchez C, Mazzucchelli G, Lambert C, <i>et al.</i> Comparison of secretome from osteoblasts derived from sclerotic versus non-sclerotic subchondral bone in OA: A pilot study. Published Online First: 2018. doi:10.1371/journal.pone.0194591 [4]Wendel M, Sommarin Y, Heinegård D. Characterization of osteoadherin - A novel, cell binding keratan sulfate proteoglycan from bone. Acta Orthop. 1995. doi:10.3109/17453679509157655 [5]Sommarin Y, Wendel M, Shen Z, <i>et al.</i> Osteoadherin, a cell-binding keratan sulfate proteoglycan in bone, belongs to the family of leucine-rich repeat proteins of the extracellular matrix. <i>Journal of Biological Chemistry</i> Published Online First: 1998. doi:10.1074/jbc.273.27.16723 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.